tbuckley/cabot-search huggingface dataset:
Skeletal Outcomes in Children and Young Adults with Glomerular Disease
Authors: Amy J. Goodwin Davies, Rui Xiao, Hanieh Razzaghi, L. Charles Bailey, Levon Utidjian, Caroline Gluck, Daniel Eckrich, Bradley P. Dixon, Sara J. Deakyne Davies, Joseph T. Flynn, Daksha Ranade, William E. Smoyer, Melody Kitzmiller, Vikas R. Dharnidharka, Brianna Magnusen, Mark Mitsnefes, Michael Somers, Donna J. Claes, Evanette K. Burrows, Ingrid Y. Luna, Susan L. Furth, Christopher B. Forrest, Michelle R. Denburg
Journal: Journal of the American Society of Nephrology (2022)

Children with glomerular disease have unique risk factors for compromised bone health. Studies addressing skeletal complications in this population are lacking.This retrospective cohort study utilized data from PEDSnet, a national network of pediatric health systems with standardized electronic health record data for more than 6.5 million patients from 2009 to 2021. Incidence rates (per 10,000 person-years) of fracture, slipped capital femoral epiphysis (SCFE), and avascular necrosis/osteonecrosis (AVN) in 4598 children and young adults with glomerular disease were compared with those among 553,624 general pediatric patients using Poisson regression analysis. The glomerular disease cohort was identified using a published computable phenotype. Inclusion criteria for the general pediatric cohort were two or more primary care visits 1 year or more apart between 1 and 21 years of age, one visit or more every 18 months if followed >3 years, and no chronic progressive conditions defined by the Pediatric Medical Complexity Algorithm. Fracture, SCFE, and AVN were identified using SNOMED-CT diagnosis codes; fracture required an associated x-ray or splinting/casting procedure within 48 hours.We found a higher risk of fracture for the glomerular disease cohort compared with the general pediatric cohort in girls only (incidence rate ratio [IRR], 1.6; 95% CI, 1.3 to 1.9). Hip/femur and vertebral fracture risk were increased in the glomerular disease cohort: adjusted IRR was 2.2 (95% CI, 1.3 to 3.7) and 5 (95% CI, 3.2 to 7.6), respectively. For SCFE, the adjusted IRR was 3.4 (95% CI, 1.9 to 5.9). For AVN, the adjusted IRR was 56.2 (95% CI, 40.7 to 77.5).Children and young adults with glomerular disease have significantly higher burden of skeletal complications than the general pediatric population.
Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction
Authors: Rachel L. Kember, Rachel Vickers-Smith, Heng Xu, Sylvanus Toikumo, Maria Niarchou, Hang Zhou, Emily E. Hartwell, Richard C. Crist, Christopher T. Rentsch, Lea K. Davis, Amy C. Justice, Sandra Sanchez-Roige, Kyle M. Kampman, Joel Gelernter, Henry R. Kranzler
Journal: Nature Neuroscience (2022)
Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice
Authors: Yohan S. S. Auguste, Austin Ferro, Jessica A. Kahng, Andre M. Xavier, Jessica R. Dixon, Uma Vrudhula, Anne-Sarah Nichitiu, Daniele Rosado, Tse-Luen Wee, Ullas V. Pedmale, Lucas Cheadle
Journal: Nature Neuroscience (2022)

Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes throughout life, but the functions of OPCs are not limited to oligodendrogenesis. Here we show that OPCs contribute to thalamocortical presynapse elimination in the developing and adult mouse visual cortex. OPC-mediated synapse engulfment increases in response to sensory experience during neural circuit refinement. Our data suggest that OPCs may regulate synaptic connectivity in the brain independently of oligodendrogenesis.
Complementary task representations in hippocampus and prefrontal cortex for generalizing the structure of problems
Authors: Veronika Samborska, James L. Butler, Mark E. Walton, Timothy E. J. Behrens, Thomas Akam
Journal: Nature Neuroscience (2022)

Humans and other animals effortlessly generalize prior knowledge to solve novel problems, by abstracting common structure and mapping it onto new sensorimotor specifics. To investigate how the brain achieves this, in this study, we trained mice on a series of reversal learning problems that shared the same structure but had different physical implementations. Performance improved across problems, indicating transfer of knowledge. Neurons in medial prefrontal cortex (mPFC) maintained similar representations across problems despite their different sensorimotor correlates, whereas hippocampal (dCA1) representations were more strongly influenced by the specifics of each problem. This was true for both representations of the events that comprised each trial and those that integrated choices and outcomes over multiple trials to guide an animal's decisions. These data suggest that prefrontal cortex and hippocampus play complementary roles in generalization of knowledge: PFC abstracts the common structure among related problems, and hippocampus maps this structure onto the specifics of the current situation.
Thalamus-driven functional populations in frontal cortex support decision-making
Authors: Weiguo Yang, Sri Laasya Tipparaju, Guang Chen, Nuo Li
Journal: Nature Neuroscience (2022)

Neurons in frontal cortex exhibit diverse selectivity representing sensory, motor and cognitive variables during decision-making. The neural circuit basis for this complex selectivity remains unclear. We examined activity mediating a tactile decision in mouse anterior lateral motor cortex in relation to the underlying circuits. Contrary to the notion of randomly mixed selectivity, an analysis of 20,000 neurons revealed organized activity coding behavior. Individual neurons exhibited prototypical response profiles that were repeatable across mice. Stimulus, choice and action were coded nonrandomly by distinct neuronal populations that could be delineated by their response profiles. We related distinct selectivity to long-range inputs from somatosensory cortex, contralateral anterior lateral motor cortex and thalamus. Each input connects to all functional populations but with differing strength. Task selectivity was more strongly dependent on thalamic inputs than cortico-cortical inputs. Our results suggest that the thalamus drives subnetworks within frontal cortex coding distinct features of decision-making.
pH-activatable oxidative stress amplifying dissolving microneedles for combined chemo-photodynamic therapy of melanoma
Authors: Yanjuan Huang, Hualu Lai, Jingwen Jiang, Xiaoyu Xu, Zishan Zeng, Lingling Ren, Qiuxing Liu, Meixu Chen, Tao Zhang, Xin Ding, Chunshun Zhao, Shengmiao Cui
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Photodynamic therapy (PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation, but the strong hydrophobicity and poor tumor selectivity of photosensitizers, as well as the oxygen-consuming properties of PDT, leading to unsatisfactory therapeutic outcomes. Herein, a tumor acidic microenvironment activatable dissolving microneedle ([email protected]) was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification. The versatile [email protected] was fabricated by crosslinking a self-synthesized protoporphyrin (PpIX)-ADH-hyaluronic acid (HA) conjugate HA-ADH-PpIX with "iron reservoir" PA-Fe3+ complex in the needle tip via acylhydrazone bond formation, and dihydroartemisinin (DHA) was concurrently loaded in the hydrogel network. HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect. [email protected] with sharp needle tip, efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites, where the acidic pH triggered the degradation of microneedles, enabling Fe-activated and DHA-mediated oxidation treatment, as evidenced by abundant reactive oxygen species (ROS) generation. Moreover, under light irradiation, a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation. Importantly, the Fe-catalyzed ROS production of DHA was oxygen-independent, which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells. This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodynamic therapy of melanoma.
Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response
Authors: Alex Adams, Vipin Gupta, Waled Mohsen, Thomas P Chapman, Deloshaan Subhaharan, Pradeep Kakkadasam Ramaswamy, Sudheer Kumar, Saurabh Kedia, Colleen GC McGregor, Tim Ambrose, Bruce D George, Rebecca Palmer, Oliver Brain, Alissa Walsh, Vineet Ahuja, Simon P L Travis, Jack Satsangi
Journal: Gut (2022)

We aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission.Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015-2020, n=110; All India Institute of Medical Sciences, New Delhi 2018-2020, n=62).In the 2015-2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992-1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992-1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%-11%.Emergency colectomy rates for ASC have halved in 25 years to 8%-15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.
Advancing human gut microbiota research by considering gut transit time
Authors: Nicola Procházková, Gwen Falony, Lars Ove Dragsted, Tine Rask Licht, Jeroen Raes, Henrik M Roager
Journal: Gut (2022)

Accumulating evidence indicates that gut transit time is a key factor in shaping the gut microbiota composition and activity, which are linked to human health. Both population-wide and small-scale studies have identified transit time as a top covariate contributing to the large interindividual variation in the faecal microbiota composition. Despite this, transit time is still rarely being considered in the field of the human gut microbiome. Here, we review the latest research describing how and why whole gut and segmental transit times vary substantially between and within individuals, and how variations in gut transit time impact the gut microbiota composition, diversity and metabolism. Furthermore, we discuss the mechanisms by which the gut microbiota may causally affect gut motility. We argue that by taking into account the interindividual and intraindividual differences in gut transit time, we can advance our understanding of diet–microbiota interactions and disease-related microbiome signatures, since these may often be confounded by transient or persistent alterations in transit time. Altogether, a better understanding of the complex, bidirectional interactions between the gut microbiota and transit time is required to better understand gut microbiome variations in health and disease.
Holistic healthcare in inflammatory bowel disease: time for patient-centric approaches?
Authors: Padhmanand Sudhakar, Judith Wellens, Bram Verstockt, Marc Ferrante, João Sabino, Séverine Vermeire
Journal: Gut (2022)

Inflammatory bowel disease (IBD) is an emerging global disease characterised by chronic inflammation of the gastrointestinal tract. However, IBD is also manifested by several extraintestinal symptoms which, along with the intestinal symptoms, impact on the mental and emotional well-being of patients. Despite therapeutic advancements, only one-third of the diagnosed patients receiving approved medical treatments achieve short-term to medium-term remission. Consequently, patients who do not get successfully treated might resort to using complementary and alternative approaches to manage their symptoms, with or without consulting their treating clinician. Despite their possible potential, such approaches have various risks stemming from unknown adverse reactions and possible interference with medically approved therapies. In this study, we present the results of a well-performed literature review where we included randomised clinical trials which have assessed the efficacy of complementary approaches and dietary therapy on at least one of the following four outcomes: clinical remission, endoscopic remission, modulation of molecular biomarkers or quality of life metrics. By pointing out intraoutcome and interoutcome concordance, we identified possible candidates for clinical adoption and further study in larger randomised clinical trials covering the broad spectrum of IBD heterogeneity. We finally proposed a patient-centric clinical care model and a series of recommendations for stakeholders, with special attention to complementary approaches and dietary strategies, aimed at achieving holistic remission.
CAR T cells targeting <i>Aspergillus fumigatus</i> are effective at treating invasive pulmonary aspergillosis in preclinical models
Authors: Michelle Seif, Tamara Katharina Kakoschke, Frank Ebel, Marina Maria Bellet, Nora Trinks, Giorgia Renga, Marilena Pariano, Luigina Romani, Beeke Tappe, David Espie, Emmanuel Donnadieu, Kerstin Hünniger, Antje Häder, Markus Sauer, Diane Damotte, Marco Alifano, P. Lewis White, Matthijs Backx, Thomas Nerreter, Markus Machwirth, Oliver Kurzai, Sabrina Prommersberger, Hermann Einsele, Michael Hudecek, Jürgen Löffler
Journal: Science Translational Medicine (2022)

Aspergillus fumigatus is a ubiquitous mold that can cause severe infections in immunocompromised patients, typically manifesting as invasive pulmonary aspergillosis (IPA). Adaptive and innate immune cells that respond to A. fumigatus are present in the endogenous repertoire of patients with IPA but are infrequent and cannot be consistently isolated and expanded for adoptive immunotherapy. Therefore, we gene-engineered A. fumigatus –specific chimeric antigen receptor (Af-CAR) T cells and demonstrate their ability to confer antifungal reactivity in preclinical models in vitro and in vivo. We generated a CAR targeting domain AB90-E8 that recognizes a conserved protein antigen in the cell wall of A. fumigatus hyphae. T cells expressing the Af-CAR recognized A. fumigatus strains and clinical isolates and exerted a direct antifungal effect against A. fumigatus hyphae. In particular, CD8 + Af-CAR T cells released perforin and granzyme B and damaged A. fumigatus hyphae. CD8 + and CD4 + Af-CAR T cells produced cytokines that activated macrophages to potentiate the antifungal effect. In an in vivo model of IPA in immunodeficient mice, CD8 + Af-CAR T cells localized to the site of infection, engaged innate immune cells, and reduced fungal burden in the lung. Adoptive transfer of CD8 + Af-CAR T cells conferred greater antifungal efficacy compared to CD4 + Af-CAR T cells and an improvement in overall survival. Together, our study illustrates the potential of gene-engineered T cells to treat aggressive infectious diseases that are difficult to control with conventional antimicrobial therapy and support the clinical development of Af-CAR T cell therapy to treat IPA.
Facilitating early parent-infant emotional connection improves cortical networks in preterm infants
Authors: Pauliina Yrjölä, Michael M. Myers, Martha G. Welch, Nathan J. Stevenson, Anton Tokariev, Sampsa Vanhatalo
Journal: Science Translational Medicine (2022)

Exposure to environmental adversities during early brain development, such as preterm birth, can affect early brain organization. Here, we studied whether development of cortical activity networks in preterm infants may be improved by a multimodal environmental enrichment via bedside facilitation of mother-infant emotional connection. We examined functional cortico-cortical connectivity at term age using high-density electroencephalography recordings in infants participating in a randomized controlled trial of Family Nurture Intervention (FNI). Our results identify several large-scale, frequency-specific network effects of FNI, most extensively in the alpha frequency in fronto-central cortical regions. The connectivity strength in this network was correlated to later neurocognitive performance, and it was comparable to healthy term-born infants rather than the infants receiving standard care. These findings suggest that preterm neurodevelopmental care can be improved by a biologically driven environmental enrichment, such as early facilitation of direct human connection.
Constructing 2D maps of human spinal cord activity and isolating the functional midline with high-density microelectrode arrays
Authors: Samantha M. Russman, Daniel R. Cleary, Youngbin Tchoe, Andrew M. Bourhis, Brittany Stedelin, Joel Martin, Erik C. Brown, Xinlian Zhang, Aaron Kawamoto, Won Hyung A. Ryu, Ahmed M. Raslan, Joseph D. Ciacci, Shadi A. Dayeh
Journal: Science Translational Medicine (2022)

Intraoperative neuromonitoring (IONM) is a widely used practice in spine surgery for early detection and minimization of neurological injury. IONM is most commonly conducted by indirectly recording motor and somatosensory evoked potentials from either muscles or the scalp, which requires large-amplitude electrical stimulation and provides limited spatiotemporal information. IONM may inform of inadvertent events during neurosurgery after they occur, but it does not guide safe surgical procedures when the anatomy of the diseased spinal cord is distorted. To overcome these limitations and to increase our understanding of human spinal cord neurophysiology, we applied a microelectrode array with hundreds of channels to the exposed spinal cord during surgery and resolved spatiotemporal dynamics with high definition. We used this method to construct two-dimensional maps of responsive channels and define with submillimeter precision the electrophysiological midline of the spinal cord. The high sensitivity of our microelectrode array allowed us to record both epidural and subdural responses at stimulation currents that are well below those used clinically and to resolve postoperative evoked potentials when IONM could not. Together, these advances highlight the potential of our microelectrode arrays to capture previously unexplored spinal cord neural activity and its spatiotemporal dynamics at high resolution, offering better electrophysiological markers that can transform IONM.
The pancreatic clock is a key determinant of pancreatic fibrosis progression and exocrine dysfunction
Authors: Weiliang Jiang, Linzi Jin, Dapeng Ju, Zhanjun Lu, Chuanyang Wang, Xingya Guo, Haijiao Zhao, Shien Shen, Zhiyuan Cheng, Jie Shen, Guanzhao Zong, Jiahui Chen, Kai Li, Lijuan Yang, Zhijian Zhang, Yun Feng, Jia Z. Shen, Eric Erquan Zhang, Rong Wan
Journal: Science Translational Medicine (2022)

Chronic pancreatitis (CP) is characterized by progressive fibrosis and exocrine dysregulation, which have long been considered irreversible. As a peripheral oscillator, the pancreas harbors autonomous and self-sustained timekeeping systems in both its endocrine and exocrine compartments, although the role of the latter remains poorly understood. By using different models of CP established in mice with dysfunctional pancreatic clocks, we found that the local clock played an important role in CP pathology, and genetic or external disruption of the pancreatic clock exacerbated fibrogenesis and exocrine insufficiency. Mechanistically, an impaired retinoic acid receptor–related orphan receptor A (Rora)/nuclear receptor subfamily 1, group D, member 1 (Nr1d1)/aryl hydrocarbon receptor nuclear translocator-like (Arntl or Bmal1) loop, called the circadian stabilizing loop, resulted in the deficiency of pancreatic Bmal1, which was responsible for controlling the fibrogenic properties of pancreatic stellate cells (PSCs) and for rewiring the function of acinar cells in a clock–TGF signaling–IL-11/IL-11RA axis–dependent manner. During PSC activation, the antagonistic interaction between Nr1d1 and Rora was unbalanced in response to the loss of cytoplasmic retinoid-containing lipid droplets. Patients with CP also exhibited reduced production of endogenous melatonin. Enhancing the clock through pharmacological restoration of the circadian stabilizing loop using a combination of melatonin and the Rora agonist SR1078 attenuated intrapancreatic pathological changes in mouse models of CP. Collectively, this study identified a protective role of the pancreatic clock against pancreatic fibrosis and exocrine dysfunction. Pancreatic clock–targeted therapy may represent a potential strategy to treat CP.
Improving breast cancer diagnostics with deep learning for MRI
Authors: Jan Witowski, Laura Heacock, Beatriu Reig, Stella K. Kang, Alana Lewin, Kristine Pysarenko, Shalin Patel, Naziya Samreen, Wojciech Rudnicki, Elżbieta Łuczyńska, Tadeusz Popiela, Linda Moy, Krzysztof J. Geras
Journal: Science Translational Medicine (2022)

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has a high sensitivity in detecting breast cancer but often leads to unnecessary biopsies and patient workup. We used a deep learning (DL) system to improve the overall accuracy of breast cancer diagnosis and personalize management of patients undergoing DCE-MRI. On the internal test set ( n = 3936 exams), our system achieved an area under the receiver operating characteristic curve (AUROC) of 0.92 (95% CI: 0.92 to 0.93). In a retrospective reader study, there was no statistically significant difference ( P = 0.19) between five board-certified breast radiologists and the DL system (mean ΔAUROC, +0.04 in favor of the DL system). Radiologists’ performance improved when their predictions were averaged with DL’s predictions [mean ΔAUPRC (area under the precision-recall curve), +0.07]. We demonstrated the generalizability of the DL system using multiple datasets from Poland and the United States. An additional reader study on a Polish dataset showed that the DL system was as robust to distribution shift as radiologists. In subgroup analysis, we observed consistent results across different cancer subtypes and patient demographics. Using decision curve analysis, we showed that the DL system can reduce unnecessary biopsies in the range of clinically relevant risk thresholds. This would lead to avoiding biopsies yielding benign results in up to 20% of all patients with BI-RADS category 4 lesions. Last, we performed an error analysis, investigating situations where DL predictions were mostly incorrect. This exploratory work creates a foundation for deployment and prospective analysis of DL-based models for breast MRI.